كتاب Exploiting Chemical Diversity for Drug Discovery
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منتدى هندسة الإنتاج والتصميم الميكانيكى
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 كتاب Exploiting Chemical Diversity for Drug Discovery

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كتاب Exploiting Chemical Diversity for Drug Discovery  Empty
مُساهمةموضوع: كتاب Exploiting Chemical Diversity for Drug Discovery    كتاب Exploiting Chemical Diversity for Drug Discovery  Emptyالإثنين 28 يونيو 2021, 11:57 pm

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أحضرت لكم كتاب
Exploiting Chemical Diversity for Drug Discovery
Edited by
Paul A. Bartlett
Department of Chemistry, University of California, Berkeley
Michael Entzeroth
S*Bio Pte Ltd, Singapore

كتاب Exploiting Chemical Diversity for Drug Discovery  E_c_d_10
و المحتوى كما يلي :


Contents
Section 1 Operational Developments in Chemistry
Chapter 1 The Use of Polymer-Assisted Solution-Phase
Synthesis and Automation for the
High-Throughput Preparation of
Biologically Active Compounds 3
Steven V. Ley, Mark Ladlow and
Emma Vickerstaffe
1 Introduction 3
2 PASP Synthesis Approaches to Biologically Active
Compounds 7
2.1 Applications to the Synthesis of
Commercial Drug Molecules 7
2.2 Applications of PASP to the Synthesis of
Biologically Active Natural Products 10
2.3 PASP Synthesis in the Library Production of
Biologically Active Small Molecules 12
3 Automated PASP Synthesis of Biologically Active
Molecules 19
3.1 Stepwise Automation of PASP
Synthesis in Batch Mode 19
3.2 Fully Automated PASP Synthesis of
Drug-Like Molecules in Batch Mode 21
3.3 Flow Chemistry and Automation in the
Synthesis of Drug-Like Molecules 23
4 Conclusion 28
References 28
Chapter 2 Accelerated Chemistry: Microwave,
Sonochemical, and Fluorous Phase Techniques 33
Kristofer Olofsson, Peter Nilsson and
Mats Larhed
1 Introduction 332 Microwave Enhanced Chemistry 34
2.1 General 34
2.2 Applications in Medicinal Chemistry 35
2.3 Applications in Solid-Phase Chemistry 37
3 Sonochemistry as a Means to Accelerate Synthesis 37
3.1 General 37
3.2 Organometallic Sonochemistry 38
3.3 Heterocyclic and Pericyclic Chemistry 38
3.4 Applications in Medicinal Chemistry 39
4 Fluorous Phase Techniques 40
4.1 General 40
4.2 Reagents, Linkers, and Scavengers 42
4.3 Fluorous Protecting Groups 44
4.4 Fluorous Mixture Synthesis 44
4.5 Peptides and Oligosaccharides 45
4.6 Fluorous Applications in High-Throughput
Chemistry 46
4.7 Microwave-Enhanced Fluorous Chemistry 46
5 Conclusion 48
Acknowledgements 48
References 48
Section 2 Conceptual Advances in Synthesis:
“Prospecting” – Design of Discovery
Libraries and the Search for Hits
Chapter 3 Biosynthesis of “Unnatural” Natural Products 57
Yi Tang and Chaitan Khosla
1 Introduction 57
1.1 Polyketide Assembly 58
1.2 Three Major Classes of Polyketide Synthases 60
1.3 Methods for Engineered Biosynthesis 60
2 Type I Polyketide Synthases 61
2.1 Modular Architecture 61
2.2 The Erythromycin Synthase 63
2.3 Engineered Biosynthesis of Multimodular
PKS Products 64
2.3.1 Domain Engineering 64
2.3.2 Module Engineering 66
2.3.3 Primer Unit Engineering and
Precursor-Directed Biosynthesis 68
2.4 Multimodular PKSs that Exhibit Special Features 70
2.5 Fungal Type I PKSs 70
xii Contents3 Type II Polyketide Synthases 72
3.1 Dissociated Architecture 72
3.2 Combinatorial Biosynthesis of
Type II Polyketides 75
3.2.1 Chain-Length Variations 76
3.2.2 Mix and Match of Tailoring Enzymes 76
3.2.3 Primer Unit Modifications 78
3.2.4 Reshuffling of Downstream
Tailoring Enzymes 80
4 Type III Polyketide Synthase 81
4.1 Type III PKS Consists of a Homodimeric
Ketosynthase 81
4.2 Engineered Biosynthesis of Type III Polyketides 84
5 Conclusions 85
Acknowledgments 86
References 86
Chapter 4 Combinatorial Synthetic Design:
The Balance of Novelty and Familiarity 91
A. Ganesan
1 Biological Macromolecules – Strength in Numbers 91
1.1 Congruence between Biological and
Chemical Space 93
1.2 The Libraries are Exhaustive within the
Defined Boundaries 93
1.3 Highly Optimized Synthesis Procedures
were Available 94
2 Oligomer Synthesis – Improving on Mother Nature 94
3 Random, Discovery, or Prospecting Libraries –
the Quest for the Universal Scaffold 96
4 Privileged Scaffolds – Look Where the
Light is Brightest 96
5 The Decoration or Synthesis of Novel Scaffolds –
Aid for the Underprivileged 97
6 Target Class Libraries – Diversity with a Purpose 100
7 Peptide and Nucleotide Libraries Redux 101
8 Lead Discovery or Drug Discovery – Size
does Matter 102
9 Natural Product Scaffolds for Combinatorial
Chemistry – Why Reinvent the Wheel? 103
10 From Natural Products to Natural Product-Like
Libraries – Hubris or Progress? 104
Contents xiii11 Lead Discovery and Combinatorial Chemistry –
What have We Learned? 105
11.1 The Drug-Discovery Process cannot be
Simplified to a Single Blueprint 106
11.2 Combinatorial Chemistry is an Extremely
Powerful Technology 106
11.3 Combinatorial Chemistry is at its Best in
Lead Optimization 107
11.4 Combinatorial Chemistry is about Making
the Compounds that Fit Your Needs,
not How They are Made 107
References 107
Chapter 5 Compound Collections: Acquisition,
Annotation, and Access 112
Reg Richardson
1 Introduction 112
2 Commercial Offerings 113
3 Companies Providing Non-Proprietary,
Non-Parallel Synthesised Libraries
(Shared-Pool/‘Collected Collections’) 115
4 Companies Providing In-House Designed,
Parallel Synthesised Libraries 117
5 Compound Selection and Database Filtering 119
6 Sub-structure Similarity/Dissimilarity 119
7 Pharmacophore Analysis 120
8 Annotation 124
9 Lipinski Rule-of-Five (LRoF) 126
10 Topological Polar Surface Area (tPSA) and
Blood–Brain-Barrier Permeability (Log BB) 126
11 Solubility 128
12 Examples of the Use of Chemical Annotation and
Pharmacophore-Based Lead-Hopping 129
13 Compound Acquisition 132
Acknowledgments 134
References 134
Chapter 6 Chemical Diversity: Definition and
Quantification 137
Alan C. Gibbs and Dimitris K. Agrafiotis
1 Introduction 137
xiv Contents2 Diversity Metrics 138
2.1 Distance-Based Metrics 138
2.2 Cell-Base Diversity Metrics 140
2.3 Variance-Based Diversity Metrics 142
3 Molecular Description 143
3.1 Two-Dimensional Descriptors 143
3.2 Three-Dimensional Descriptors 145
3.3 Physicochemical and Electronic Descriptors 146
3.4 Descriptor Selection 146
4 Dimensionality Reduction 147
4.1 Principle Component Analysis 148
4.2 Singular-Value Decomposition 148
4.3 Factor Analysis (FA) 149
4.4 MultiDimensional Scaling 149
4.5 Stochastic Proximity Embedding 150
5 Subset Selection and Classification 151
5.1 Clustering 152
5.2 Partitioning Methods 153
5.3 Experimental Design 154
5.4 Reagent-Based Versus Product-Based Design 155
5.5 Random Versus Rational Design 155
6 Conclusion 156
Abbreviations 156
References 156
Section 3 Conceptual Advances in Synthesis:
“Mining” – Turning a Hit into a Lead
Chapter 7 Focused Libraries: The Evolution in Strategy
from Large-Diversity Libraries to the
Focused Library Approach 163
Ruben Tommasi and Ivan Cornella
1 Introduction 163
2 A Synergistic, Multidisciplinary Approach to
Library Conception 164
2.1 Improvements in Synthetic Methods 164
2.2 Impact of In Silico Tools for Library Design 165
2.3 Influence of Biology in Library Design 166
3 Library Design Concepts 167
3.1 Impact of Diversity on Library Design 167
3.2 Diversity-Oriented Synthesis in Prospecting
Library Design 168
3.3 Target-Oriented Library Design 168
3.4 Focus on Drug-Like Libraries 170
Contents xv4 Focused Libraries 170
4.1 Libraries Focused on Pharmacophore Models 170
4.2 Libraries Focused on Privileged Structures 172
4.3 Libraries Focused on Target Classes 172
4.3.1 GPCR-Targeted Libraries 173
4.3.2 Kinase-Targeted Libraries 174
4.3.3 Natural Product-Based Focused
Libraries 174
4.4 Early Optimization or Hit-to-Lead Libraries 177
5 Summary 179
References 179
Chapter 8 Translating Peptides into Small Molecules 184
Gerd Hummel, Ulrich Reineke and Ulf Reimer
1 Peptides as Drugs: The Good, the Bad and the Ugly 184
2 Origin of Biologically Active Peptides 185
3 General Strategy for Translating Peptides into
Small Molecules 186
4 Tailoring Peptide Sequences for their Translation
into Small Molecules 186
5 Transformation of Peptide Ligands into Small
Molecules using Computational Approaches 191
6 Conclusion 198
References 198
Section 4 Operational Developments in Screening and High
Throughput Assays
Chapter 9 High-Density Plates, Microarrays, Microfluidics 203
Christof Fattinger and Gregor Dernick
1 Functional High-Density Well Plates for
High-Throughput Assays 204
1.1 Sample Plates for Low-Volume
High-Throughput Screening 205
1.2 High-Density Assay Plates for HTS and
Multidimensional Compound Profiling 206
1.3 Technical, Biological, and Economical Limits
for Assay Miniaturization in High-Density
Plates 208
1.4 384-Microtube Plate for High-Throughput
Retrieval of Compound Subsets 210
1.5 Sample Management for HTS and
Multidimensional Compound Profiling 211
xvi Contents2 Parallel Liquid Handling of Low-Volume Samples 215
2.1 Pipetting and Dispensing in High-Density
Plates 215
2.2 High-Throughput Aliquoting of the
HTS Library 219
2.3 A Microfluidic Well Plate for
High-Throughput Solid/Liquid Separations 222
3 Microarray Assays on Chips 223
3.1 Microchannel Assay: A New Generation of
Miniaturized Multiplexed Bioassays 226
4 Prospects for Multiparameter Assays 229
Acknowledgment 231
References 231
Chapter 10 Fluorescence Technologies for the
Investigation of Chemical Libraries 233
Eric Trinquet and Gérard Mathis
1 Introduction 233
2 Dissociation-Enhanced Lanthanide
Fluoroimmunoassay 234
3 Enzyme Fragment Complementation 236
4 Fluorescence Polarization 236
5 Fluorescence Correlation Spectroscopy 238
6 Amplified Luminescent Proximity
Homogeneous Assay (AlphaScreen™) 238
7 Fluorescence Resonance Energy Transfer 239
8 Bioluminescence Resonance Energy Transfer 241
9 Homogeneous Time Resolved Fluorescence 241
10 Conclusion 244
References 245
Chapter 11 The Use of Genetically Engineered Cell-Based
Assays in in-vitro Drug Discovery 247
Renate Schnitzer and Wolfgang Sommergruber
1 Introduction 247
2 Genetic Engineering for Cell-Based Assays 248
2.1 Expression Systems 248
2.2 Choice of Cell Line and Promoter 249
2.3 Chromosomal Integration Site 250
3 Reporter-Based Assays 250
3.1 Chloramphenicol Acetyl Transferase,
Secreted Placental Alkaline
Phosphatase, β-Galactosidase 251
Contents xvii3.2 Green Fluorescent Protein 252
3.3 Luciferase 252
3.4 β-Lactamase 253
3.5 Examples of Applications 254
4 Assays to Measure Intracellular Calcium 256
5 Assays to Monitor Protein–Protein Interactions 257
5.1 Bioluminescence Resonance Energy Transfer
and Fluorescence Resonance Energy Transfer 257
5.2 Enzyme Complementation 258
6 Conclusions and Outlook 259
References 260
Chapter 12 NMR-Based Screening: A Powerful Tool in
Fragment-Based Drug Discovery 263
Jochen Klages, Murray Coles and Horst Kessler
1 Introduction 263
2 NMR Screening: General Aspects 266
3 Ligand- vs. Target-Detected Methods 268
3.1 Sample Requirements 268
4 Incorporation of NMR into the Drug Discovery
Process 269
4.1 Hit Finding 270
4.1.1 STD and WaterLOGSY 270
4.1.2 Libraries of 19F-Containing Ligands 272
4.2 Hit Validation 273
4.2.1 Chemical Shift Mapping 273
4.3 Hit Optimization 274
4.3.1 Chemical Shift Mapping 274
4.3.2 Competition-Based Screening 275
4.3.3 Paramagnetic Spin Labels 276
5 Representative Case Studies 277
5.1 Fluorine Screening 277
5.2 SAR-by-NMR 282
5.3 Saturation Transfer Double Difference 285
6 Conclusion 287
References 288
Chapter 13 Screening Chemical Microarrays: Methods
and Applications 291
Pappanaicken R. Kumaresan and Kit S. Lam
1 Introduction 291
1.1 In situ Synthesis of Peptide and
Non-Peptide Microarrays 293
xviii Contents1.2 Spotting of Pre-Synthesized Small
Molecules and Peptides 293
1.3 Carbohydrate Microarrays 293
1.4 One-Bead-One-Compound
Combinatorial Library
Bead-Arrays 294
2 Screening of Chemical Microarrays 295
2.1 Labeling Methods 296
2.1.1 Fluorescence Method 296
2.1.2 Chemiluminescence Method 297
2.1.3 Radiolabeling Methods 297
2.1.4 Colorimetric Methods 297
2.2 Label-Free Optical and Mass
Spectrometry Methods 298
2.2.1 Surface Plasmon Resonance 298
2.2.2 Oblique-Incidence Optical
Reflectivity Difference
Microscopy 298
2.2.3 Surface-Enhanced Laser
Desorption/Ionization Mass
Spectrometry 298
2.2.4 Atomic Force Microscopy 299
2.2.5 Fiber-Optic Bead Methods 299
2.2.6 Laser-Detection Methods 299
2.2.7 Electrochemical Biosensor
Method 299
2.2.8 Cell-Based Assays 300
3 Applications of Chemical Microarrays 300
3.1 Basic Science Applications 301
3.1.1 Protein-Binding Arrays 301
3.1.2 Carbohydrate Microarrays for Cell
Receptors 302
3.1.3 Cell-Signaling Arrays 302
3.1.4 Enzyme Substrate/Inhibitor Arrays 303
3.1.5 Chemical-Detection Arrays 303
3.2 Medical Applications 304
3.2.1 Diagnostic Arrays 304
3.2.2 Immunological Arrays 304
3.2.3 Cell-Binding Arrays 305
3.2.4 Drug-Discovery Arrays 305
4 Conclusion 306
Acknowledgments 306
References 307
Contents xixSection 5 Conceptual Advances in Lead Evaluation:
Screen Early and Often
Chapter 14 Screen/Counter-Screen: Early Assessment
of Selectivity 315
Martyn N. Banks, Litao Zhang and
John G. Houston
1 Introduction 315
2 Approaches Used for Selection of Drug Candidates 317
2.1 Lead Evaluation and Liability Profiling 317
2.1.1 ADME Liability Profiling 318
2.1.2 The Lead Evaluation Process:
Technologies and Methods 319
2.2 Specificity of Drug Candidates and the
Construction of In Vitro Specificity Panels 323
2.2.1 Receptors 323
2.2.2 Protein Kinases 328
2.2.3 Ion Channels 331
3 Summary 332
References 332
Chapter 15 Concepts for In Vitro Profiling: Drug
Activity, Selectivity and Liability 336
Michael B. Bolger, Robert Fraczkiewicz,
Michael Entzeroth and Boyd Steere
1 Introduction 336
2 Physicochemical Parameters 339
2.1 Partition Coefficient 339
2.2 pKa 340
2.3 Solubility 343
2.3.1 Thermodynamic Solubility 343
2.3.2 To Buffer or not to Buffer 345
3 Permeability 348
4 Metabolism 350
5 Protein Binding 353
6 Toxicity 354
6.1 Cell Viability: MTS Assay for In Vitro
Cytotoxicity 355
6.2 Membrane Damage: Release of LDH
(Lactate Dehydrogenase) 355
6.3 Induction of Apoptosis: Caspase Activity 355
6.4 HERG Potassium Channel Interaction 355
xx Contents6.5 Microarrays 356
6.6 Recent Approaches 357
7 Investigation of Compound Selectivity 357
8 Conclusion and Outlook 357
References 360
Chapter 16 In Silico Surrogates for In Vivo Properties:
Profiling for ADME and
Toxicological Behavior 364
Michael B. Bolger, Robert Fraczkiewicz
and Boyd Steere
1 In Silico Surrogates for In Vivo Properties 364
1.1 Molecular Descriptor Generation 365
1.2 Modeling Methods 366
1.3 Multiple Linear Regression 366
1.4 Partial Least Squares 367
1.5 Artificial Neural Network 367
1.6 Support Vector Machines 368
2 Estimation of Biopharmaceutical Properties 369
2.1 Partition Coefficient 369
2.2 pKa 369
2.3 Permeability 374
2.4 Solubility 374
2.5 Protein Binding 376
3 Estimation of Pharmacokinetic Properties 377
3.1 Clearance 377
3.2 Volume of Distribution 377
3.3 Metabolism 378
4 Estimation of Toxicological Properties 379
5 Integration of Surrogate Data and Estimations
with Physiological Simulation 380
References 381
Chapter 17 Uses of High Content Screening in
Chemical Optimization 386
Francesca Casano, Zhuyin Li and
Tina Garyantes
1 Introduction 386
2 When is HCS Used 387
3 HCS Systems 388
3.1 Limitations of HCS 388
3.2 How to Pick an HCS System 389
Contents xxi4 Examples Show the Power of HCS 390
4.1 Example 1: NF-kB Nuclear Translocation
Assay (from Prelux) 390
4.2 Example 2: Characterization of Apoptosis
Pathways Using High-Throughput
Image-Based Assays (from Prelux) 394
4.3 Example 3: Gap Junction Inhibitors
(from sanofi-aventis) 400
5 Summary 402
References 404
Subject Index
absorbance, 322
absorption, 339, 365
gastrointestinal, 375
ACAT model, see model, advanced
compartmental absorption and
transit
acceptor
hydrogen-bond, 374
ACP, see acyl carrier protein
activity
mitochondrial, 355
actuator
piezo, 225
acyl carrier protein, 60
adenosine monophosphate
cyclic, 325
adenosine receptor ligands, 131
adenylate cyclase, 325
ADME, 318, 348, 349
aequorin, 326
AFM, see atomic force microscopy
agonist, 325
air gap trailing (TAG), 220
albumin
human serum, 353
aliquot
liquid, 213
microliter, nanoliter, 215, 219
alkaline phosphatase, 298
allophycocyanin, 242
alphascreen, see assay, amplified luminescent proximity homogeneous
Ames, 379
aminotransferase, 63, 75
analysis
FACS, 253
fluorescence intensity distribution
(FIDA), 208, 238, 326
maximum redundancy (MRA), 367
principal component (PCA), 148,
150, 165, 367
sensitivity, 365
analytics
LC/MS/MS, 222
angiogenesis, 254
angiotensin-II receptor antagonists
microwave synthesis, 36
anisotropy
fluorescence, 208, 233
ANN, see network, artificial neural
annotation, 124, 129
antagonist, see also G-protein coupled
receptor
cholecystokinin, 172
urotensin-II receptor, 195
antibiotic, 306
antibody, 226, 297, 298, 300
antioxidant, 239
apoptosis, 328, 390, 394, 395, 397–400
aptamer, 101
aromatase, 75
array, 225, 230
cell-binding, 305
cell-signalling, 302
chemical-detection, 303
drug discovery, 305
glycoconjugated, 294
monosaccharide, 303
oligosaccharide, 294
polysaccharide, 294
protein-binding, 302
SPOT, 293
arrest
cell cycle, 390
aspiration, 216
assay
Subject Indexamplified luminescent proximity
homogeneous, 238, 239
binding, 295
cell-based, 327
cell-binding, 296, 299
colorimetric, 206, 207
fluorescence, 207, 252
homogeneous, 206, 236
kinase, 297
microfluidic, 229
microtiter plate-based, 209
optical, 206
parallel artificial membrane permeation (PAMPA), 350
peptidase, 297, 303
radioactive, 206
reporter-based, 250, 255, 256, 326
scintillation proximity (SPA), 326,
328, 329, 331
asthma, 390
atomic force microscopy (AFM), 299
augmented atoms, 143
autofluorescence, 244
automated synthesis, 19, 21, 23
automation, 315, 320
autoradiography, 297
background
fluorescence, 208
baculovirus, 248
BCS, see classification system, biopharmacutical
BCUT parameters, 128
β-cyclodextrin
chromatography column, 42
bead, 230, 291
bead array, 294, 295, 301
benzodiazepine, 172
library, 97
β-galactosidase, 236, 251, 258, 259
Biginelli condensation
sonochemical, 39
bilayer
lipid, 340
membrane, 339
binary descriptors, 139
binding
conformation, 188
energy, 371
plasma protein, 376, 377
protein, 353
radioligand, 356
site, ATP, 329
binning, 142, 153
biocatalysis
sonochemistry, 40
biochip, 304
biological space, 169
biologically active molecules, synthesis, 7, 12, 19
biomarker, 304, 356
biosynthesis
combinatorial, 57, 67, 77
engineered, 57, 60, 65, 84
erythromycin, 62
lovastatin, 70, 71
natural products, 57
precursor-directed, 68, 80
tyllosin, 62
β-lactamase, 251, 253, 254, 255
blood-brain barrier, 126
bond
rotatable, 338
bowel disease
inflammatory, 390
BRET, see energy transfer, bioluminescence resonance
CADD, see computer-assisted drug
design
calcium
intracellular, 256, 325, 326, 332
calmodulin, 302
caloporoside
sonochemical synthesis, 40
camera
charge-coupled device (CCD), 297,
298, 322
cAMP, see adenosine monophosphate,
cyclic
capacity
binding, 353
406 Subject Indexcapillary pump, 227
carbohydrates
sonochemical synthesis, 40
carcinogen, 380
cardiotoxicity, 356
caspase, 395–399
caspase-3, 355
caspase-7, 355
CAT, see transferase, chloramphenicol
acetyl
catch-and-release, 5, 19, 26, 27
CAVEAT, 192
cavitation, 37
CCD Camera, see camera, charge-coupled device
cell
antigen-presenting, 302
apoptotic, 395, 398
Caco-2, 349, 350
chinese hamster ovary (CHO), 248,
250
epithelial, 339
Mandin Darby Canine Kidney
(MDCK), 349
viability, 355
cell cycle, 328
cell death
programmed, 394
centrifugation, 209, 223
CFP, see protein, cyan fluorescent
cGMP, see guanine monophosphate,
cyclic
chemical shift, 267, 273, 274, 280, 283
chemical shift dispersion, 267
chemical shift mapping, 273
chemical space, 169
chemiluminescence, 239
chemistry
combinatorial, 336, 338
medicinal, 337, 358
microwave-enhanced, 34–37
chemotaxis, 390
cherry picking, 212
chips
microfluidic, 204
chloramphenicol, 251
CHO, see cell, chinese hamster ovary
chromatography
fluorous, 42
classification system
biopharmaceutical (BCS), 374, 375
clearance, 352, 357
click chemistry, 103
cLogP, 126
clustering, 152, 153, 165
CMV, see virus, cytomegalo
coefficient
lipophilicity, 338
partition, 338, 369
combinatorial biosynthesis, 57, 67,
77
combinatorial chemistry, 163
dynamic, 103
combinatorial library
one-bead-one-compound (OBOC),
185, 291, 294, 297–302, 305, 306
combinatorial synthesis, 14
COMET, see consortium for metabonomic toxicology
CoMFA, see comparative molecular
field analysis
Committee for Proprietary Medicinal
Products (CPMP), 356
common ion effect, 344
communication
cell-to-cell, 390, 400, 401
comparative molecular field analysis
(CoMFA), 145
complementation
enzyme fragment, 235, 258
compound acquistion, 132
compound fingerprint, 119
compound selection, 119
computer-assisted drug design
(CADD), 165
concavalin A, 303
condensation
nuclear, 397, 399
conformational constraint, 188
conformational flexibility, 188
conjugate, 302
conjugation, 351
Subject Index 407consortium for metabonomic toxicology (COMET), 353
constant
dissociation, 340, 353
ionization, 343, 365
consumption
ATP, 330
contract research organization (CRO),
357
cooperative research and development
agreement (CRADA), 380
correlation spectroscopy
fluorescence, 238
correlation time, 271
coumarin, 297
counterion, 344, 346, 347
CPMP, see committee, for Proprietary
Medicinal Products
CRADA, see cooperative research and
development agreement
CRE, see responsive element, cAMP
CRIPT, see polarization transfer, crossrelaxation-induced
CRO, see contract research organization
cross-relaxation, 271
cyclase, 75
cyclic peptide, 285
cyclin-dependent kinase-2 (CDK-2)
inhibitors, 177
cyclization scan, 188, 189
cytochrome C
release, 395, 396, 398, 399
cytochrome P450, 317, 318, 351, 378,
379
cytokine, 174
cytotoxicity, 319, 354, 355,
357, 387
database filtering, 119
DEBS (6-deoxyerythronolide-B synthase), 62, 63
deconvolution, 44, 117, 164, 186
dehydratase, 61
dehydrogenase
lactate, 355
DELFIA™, see fluoroimmunoassay,
dissociation-enhanced lanthanide
density
optical, 206
depository
Smart Compound, 213, 214
descriptor, 122, 128, 137, 139, 144
2-dimensional, 143
3-dimensional, 145
atomic, 371, 373
binary, 138, 142
continuous, 138
electronic, 375
entropy, 147
field, 145
geometric, 375
molecular, 143, 170, 365, 366
physicochemical, 146
quantum-mechanical, 371
selection, 146
topological, 143, 375, 376
descriptor space, 138, 140
design
combinatorial synthetic, 168
D-optimal, 142, 143, 154
experimental, 154
ligand-based, 192
poduct-based, 155
random vs. rational, 155
reagent-based, 155
scaffold, 168
target-oriented library, 168
detection
electrochemical biosensor, 299
fluorescence, 208, 225
laser, 299
detection methods, see screening
methods
device
piezo-driven, 225
DFM, see mean, deviation from
diffusion
molecular, 267
spin, 270
dihydropteridine library
microwave-assisted fluorous phase, 48
408 Subject Indexdimensionality reduction, 147
dimethyl sulfoxide (DMSO), 205,
206, 210, 211, 212, 219–222,
322, 345
dispensing, 216
acoustic wave, 322
low-volume, 209
dissimilarity, 138, 140
distribution, 365
volume of, 377
diversity, 100, 113, 119, 163, 167
diversity analysis, 137, 147, 152
diversity metrics, see metrics
DMPK, 353
DMSO, see dimethyl sulfoxide
domain
catalytic, 329
ligand binding, 327
domain engineering, 64, 67
donor
hydrogen-bond, 374
D-optimal design, 142, 143, 154
DOS, see synthesis, diversity-oriented
dPSA, see polar surface area,
dynamic
drug discovery, 315
drugability, 357
drug-like definitions, 125, 130, 265
duodenum, 346
dye
fluorescent, 226
EBV, see virus, Epstein-Barr
EFC, see complementation, enzyme
fragment
efficacy, 387
eigenvector, 148
electrophoresis
capillary, 341
electrophysiology
patch-clamp, 331
encoding
library, 294
energy transfer
bioluminescence resonance (BRET),
241, 242, 243, 257–259
fluorescence resonance (FRET), 208,
239, 241, 243, 244, 253, 257–259,
296, 326, 328
resonance, 257, 258
time-resolved fluorescence resonance
(DELFIA™), 331
enoylreductase, 61
EPA, 379
epitope mapping, 301
epothilone biosynthesis, 68
epothilone C
synthesis, 10, 11
erythromycin
biosynthesis, 62
synthase, 63
europium, 242, 243
evaporation, 204, 226
excretion, 365
experiments
high-throughput, 203
extraction
solid-phase (SPE), 5
three-phase liquid, 41
FA, see anisotropy, fluorescence
factor analysis, 149
false positives, 273
FCS, see spectroscopy, fluorescence
correllation
FDA (Federal Drug Adminstration),
379, 380
FI, see intensity, fluorescence
FIDA, see analysis, fluorescence intensity distribution
fingerprint
compound, 119
molecular, 167
pharmacophoric, 167
FLIPR, see plate reader, fluorescence
imaging
flow systems, 23
flow-through synthesis, 23
FLT, see measurements, fluorescence
lifetime
Fluid
gastrointestinal, 346–348
Subject Index 409FLUO-3, 256
FLUO-4, 256
FluoMar, 43
fluorescein, 222
fluorescence, 234, 236, 237, 242, 244,
322, 328, 387, 391, 394, 403
correlation, 296
intensity, 391, 400, 402
laser-induced, 296
polarization, 296
time-resolved, 208, 296, 330
fluorescence energy transfer
homogeneous time-resolved (HTRF),
234, 235, 241, 244, 296, 326, 330,
331
fluoricity, 41
fluorinated compounds, 41
fluoroimmunoassay
dissociation-enhanced lanthanide
(DELFIA), 234, 235, 242, 330
fluorophore, 207, 208
fluorous mixture synthesis (FMS), 44ff
fluorous phase chemistry, 40–47
microwave-enhanced, 46
fluorous silica, 41
fluorous solid-phase extraction
(F-SPE), 42
fluorous tag, 41, 44, 46
FMS, see fluorous mixture synthesis
FP, see polarization, fluorescence
fragmentation, 395–398
fragment-based screening, 265
FRET, see energy transfer, fluorescence resonance
F-SPE, see fluorous solid-phase extraction
gallbladder, 346
gap junction, 400–402
gastrointestinal tract, 339, 345, 346
gene expression, 248, 390
genomics, 352
genotoxicity, 354
GFP, see protein, green fluorescent
GI tract, see gastrointestinal tract
glass slides, 293, 297
glycoprotein, 304
glycotransferase, 63, 75
gold-conjugation, 298
GPCR, see receptors, G proteincoupled
G-protein coupled receptors, 170, 173,
285
antagonist, 100, 101, 196
guanine monophosphate
cyclic, 325
guanylate cyclase, 325
HCS, see screening, high-content
HCV, see virus, hepatitis C
Heck coupling
microwave-assisted fluorous phase, 47
microwave-enhanced, 35
sonochemical, 38
hepatocytes, 350, 351, 355
cryopreserved, 351
hepatotoxicity, 354–356
hERG, 331, 332, 355, 356
heterocycle synthesis
sonochemical, 39
high-density
well plates, 203, 204
high-throughput chemistry
fluorous applications, 46
histone deacetylase (HDAc) inhibitors
synthesis, 22
hit rate, 163
hit validation, 164
HIV protease inhibitors
microwave synthesis, 35, 36
Hoechst 33342, 391, 393, 397, 400
Hormone
binding, 327
dimerization, 327
HTRF, see fluorescence energy transfer, homogeneous time-resolved
HTS, see screening, high throughput
IdMOC, see system, integrated discrete
multiorgan cell culture
images
fluorescence, 208
410 Subject Indeximaging
cellular fluorescent, 248
imaging technology
digital fluorescence microscopy, 401
immune response, 390
immunoassay
sandwich, 228
index
topological, 365
inducer, 250
induction
cytochrome P450, 318, 351
inhibitor
allosteric, 329, 331
inhibitor
ATP-competitive, 329
cyclin-dependent kinase-2 (CDK2),
177
peptidase, 99, 101
phosphodiesterase-4 (PDE-4), 165
protein kinase, 329
thrombin, 193, 194
integrin, 194, 197, 285, 287
intellectual property (IP), 117, 133
intensity
fluorescence, 208, 228, 233, 236,
239
interaction
drug-drug, 319, 352
ligand, 324
ligand receptor, 325
protein-protein, 302
internalisation
receptor, 390
intestine
small, 346, 348
ion channel
ligand-gated, 331
ion channel
voltage-gated, 332
ionization, 365
ionization potential , 371
IP, see intellectual property
IRORI radiofrequency tagged system,
291
Isomap, see isometric feature mapping
isometric feature mapping (Isomap),
150, 151
isotope
NMR active, 268
Jarvis-Patrick clustering, 152
ketoreductase, 61
ketosynthase, 58, 81
kinase
assays, 297
janus (JAK), 174
library, 174
protein, 236, 328, 329
labeling methods, 296
lanthanide, 242
laser desorption/ionisation
matrix-assisted (MALDI), 222, 223
latrunculin library, 175, 176
lead discovery, 315
lead identification
microarrays, 300
lead optimisation
microarrays, 300
lead-hopping, 123, 129
liability, 327, 337, 357
library
annotation, 124
aptamer, 101
benzodiazepine, 97
combinatorial, 91, 117, 291, 294,
297, 300
deletion, 187
design, 91, 163ff
discovery, 96
drug-like, 170
encoding, 294
19F-containing, 272, 280
focused, 96, 163, 170
GPCR-targeted, 173
heterocyclic/small molecule, 293,
302
high-throughput screening (HTS),
211
hit-to-lead, 177
Subject Index 411kinase inhibitor, 100, 174
large-mixture, 163
latrunculin, 175, 176
lead-finding, 165
lead-like, 102
natural product, 103, 104
natural product-like, 168, 174
NMR screening, 270, 282
non-proprietary, 115
NP-complete, 93
oligocarbamate, 94–96
oligonucleotide, 94, 101
oligophosphate, 95, 96
parallel, 117
peptide, 92–93, 101, 185
peptoid, 94, 95
privileged scaffold, 96
prospecting, 96, 168
providers, 118
random, 96
shared-pool, 115
singleton, 165
sonochemical synthesis, 40
sparse, 117
synthesis, 4, 12, 20, 23, 27
target class, 100, 172
targeted chemical, 386
targeted, non-targeted, 115
truncation, 187
virtual, 117, 128
lifetime, 233
lifetime
fluorescence, 234, 240
ligand
19F-containing, 272, 277, 278
ligand-based design, 192
ligands
µ-opiate receptor, 178
linker
fluorous, 42, 43
safety-catch, 105
traceless, 43
Lipinski’s “rule of five”, 96, 102,
126, 170, 184, 265, 274, 337,
374, 380
lipophilicity, 365, 374
liquid handling, 203, 208, 215, 217
liver,
perfusion, 350
slices, 350, 351
loading module, 61
localization
sub-cellular, 389, 390
Log BB, 126, 127
Lonapalene
sonochemical synthesis, 40
lovastatin biosynthesis, 70
luciferase, 251, 252, 328
firefly, 253
Renilla (Rluc), 241, 252
lumazine, 278
luminescence, 330, 387
MALDI, see Laser desorption/ionisation, matrix assisted
mappicine library
fluorous mixture synthesis, 44, 45
mass spectroscopy
surface-enhanced laser
desorption/ionisation (SELDI-MS),
298, 299
mass spectroscopy, 294, 299
MDS, see multidimensional scaling
mean
deviation from (DFM), 217, 220,
221
measurement
fluorescence lifetime, 208
ion flux
membrane potential, 356
medicine, clinical, 304
personalized, 304
megasynthases, 61, 63
membrane
biological, 339
outer mitochondrial, 395
metabolism, 318, 350, 365, 377, 378
in vitro, 338, 350, 351
microsomal, 351
Phase I, 351
Phase II, 351
metabonomics, 352
412 Subject Indexmethod
quantum mechanical, 365
methyltransferase, 63, 75
metrics
cell-based, 140, 153
distance-based, 138
diversity, 138
variance-based, 142
Michaelis-Menten kinetics, 348,
352
microarray, 203, 204, 210, 217, 226,
291–293, 297, 298, 304
applications, 300
bead arrays, 294, 301
carbohydrate, 293, 294, 301–305
cell-binding, 305
cell-signaling, 302
chemical, 291, 295, 300–302, 305
chemical-detection, 303
comparison, 301
diagnostic, 304
DNA, 291, 304
drug discovery, 305
enzyme substrate/inhibitor, 303
immunological, 304
non-peptide, 293
oligonucleotide, 303
peptide, 300, 301, 302, 305
peptide/peptoid, 292, 302
planar, 292, 293, 295,300, 301
preparation, 291
protein-binding, 301
screening, 295
small-molecule, 292, 305
spatially adressable, 291, 301
spatially separable, 291, 294
SPOT, 293, 297
microconstant, 370
microdissociation, 341
microfabrication, 230
microfluidics, 210, 217
microscopy
atomic force, 299
confocal, 239, 389, 393
fluorescent, 388, 389
microsome, 350, 351
microtubes, 210
microwave synthesis, 14
microwave-enhanced chemistry, 14,
34–37
mimotope, 92
miniaturization, 203, 209, 215, 224,
229, 320
mitochondria, 395
mixture
chemical, 367
MLR, see regression, multiple linear
model
Advanced Compartmental
Absorption and Transit (ACAT),
381
predictive, 368
modelling
in silico, 377
modulation-phase, 240
modulator
selective androgen receptor (SARM),
328
module engineering, 66
molecular dynamics
ensemble, 196
molecular fingerprint, 144, 150
morphology, 396, 397, 402
MRA, see analysis, maximum redundancy
MSAR, see relationship, multiparameter structure activity
MTS, 355
multidimensional scaling (MDS), 149
multidispensing, 215
multiplexing, 226
murisolin library
fluorous mixture synthesis, 45
mutagenicity, 379
natural products
“unnatural”, 57
biosynthesis, 57
fluorous mixture synthesis, 45
polyketide, 58
synthesis, 10
NCE, see new chemical entity
Subject Index 413network
artificial neural (ANN), 367–369,
376, 377
neuraminic acid analogues
sonochemical synthesis, 39
neurotoxicity, 356
new chemical entity (NCE), 112, 336,
354, 358
NF-κB, 390, 391, 394
NMR, see resonance, nuclear magnetic
NOE, see nuclear Overhauser effect
nuclear Overhauser effect, 266, 267, 270
OBOC, see one-bead-one-compound
oblique-incidence optical reflectivity
difference (OI-RD), 298
OD, see density, optical
OI-RD, see difference, oblique-incidence optical reflectivity
oncogenesis, 390
one-bead-one-compound (OBOC)
combinatorial library, 185, 291, 294,
297–302, 305, 306
organometallic sonochemistry, 38
output
fluorescence, 233
oxygenase, 75
PAMPA, see assay, parallel artificial
membrane permeation
parallelization, 229
partition coefficient, 378
partitioning, 153, 154
PASP, see synthesis, polymer-assisted
solution phase
pathway
signalling, 250
PCA, see principle component analysis
PDMS, see poly(dimethyl)siloxane
peptidase inhibitors
synthesis, 15–18
peptide scan, 185
peptide secondary structure, 190
peptide synthesis
fluorous capping reagents, 46
peptides, 184ff
peptidomimetics, 293
peptoid, 94, 158, 292, 293
peptoid nucleic acids, 293
perceptron
multi-layer, 368
perfluorinated compounds, 41
pericyclic reactions
sonochemical, 39
permeability, 339, 340, 348, 350, 374,
375
CNS, 339
paracellular, 340, 349, 350
transcellular, 340, 349, 350
P-glycoprotein (PgP), 349
PgP, see P-glycoprotein
pH, 347–349
phage display, 185
pharmacokinetics, 352, 364
pharmacophore
3-center, 122
analysis, 119, 120, 123
definition, 170
features, 193
model, 185, 186, 192, 193
space, 113
thrombin, 193
phosholipase C, 325
phosphatase
secreted placental alkaline (SEAP),
251, 294
phosphatidylinositol-3-kinase, 325
phosphodiesterase, 325
phosphoimager, 297
phosphorylation, 303
phosphotyrosine, 282
photobleaching, 208
photon-counting, 240
pin printer, 225
pins
synthesis, 91
pipetting
low-volume, 209
384-well parallel, 220
parallel, 215
pKa, 340, 342, 369
PKS, see polyketide synthase
414 Subject Indexplate
384-well, 401, 402
plate formats, 133
plate reader
fluorescence imaging (FLIPR), 255
plates
1536-well, 204, 207, 209, 215, 219,
243, 255–256
384-microtubes, 210, 213, 214
384-well, 204–207, 209, 210, 212,
215, 219, 252, 255, 322, 388,
400–402
96-well, 207, 212, 213, 230, 321
high-density, 209, 210, 215, 217
microfluidic well, 223
polar surface area (PSA)
dynamic (dPSA), 127
topological (tPSA), 126, 127, 170
polarization
fluorescence, 208, 234–237, 296,
322, 326, 328, 330
immobilized metal ion affinity-based
(IMAP™), 331
polarization transfer
cross-relaxation-induced (CRIPT), 268
poly(dimethyl)siloxane (PDMS), 227
polyketide
aromatic, 72
assembly, 58
polyketide synthase (PKS)
bacterial, 81
chimeric, 64, 67
fungal, 70
plant, 81
primer unit, 68, 78
Type I, 58, 60
Type II, 72, 74
Type III, 81, 82
polymer-assisted solution phase
(PASP) synthesis, 4, 7, 19
polysporin synthesis, 13
portion mixing, 185
positional scanning, 186
potency, 337
potential pharmacophore point (PPP),
145
PPAR, see receptor, peroxisome proliferator-activated
PPP, see potential pharmacophore
point
precision, 217, 218, 222
prediction
in silico, 364, 371
principle component analysis (PCA),
146, 148, 165, 367
privileged structures, 172
process
drug discovery, 203
processing
parallel, 203
product
solubility, 344
profile
toxicology, 338
profiling, 317, 322, 338, 341, 357,
358
property
in vivo, 364
pharmaceutical, 357
pharmacokinetic, 337, 338
physicochemical, 337
property space, 142, 153
prospecting library, 96
protecting group
fluorous, 44
protein
cyan fluorescent (CFP), 240, 257
gap junction, 400
green fluorescent (GFP), 241, 248,
251, 252, 257, 395–399
yellow fluorescent (YFP), 240, 257
protein folding, 304
protein structure similarity clustering
(PSSC), 175
protein tyrosine phosphatase 1B
NMR screening, 282
X-ray structure, 284
proteomics, 166, 222, 352
proteosome, 390
protonation, 341
PS, see resins, polystyrene
PSA, see polar surface area
Subject Index 415PSSC, see protein structure similarity
clustering
PTP1B, see protein tyrosine phosphatase 1B
QSAR, see quantitative structure-activity
relationship
QT interval, 356
QT prolongation, 356
quantitative structure-activity relationship (QSAR), 147, 165
quantum yield, 233
quencher, 239, 241
radioisotope, 297
radioligand, 331
rate
metabolic, 352
reaction
multicomponent, 164
palladium-catalyzed, 35
phase-vanishing, 43
reactor
flow-through, 24
readout
fluorescence, 209
optical, 209
reagents
fluorous, 42
polymer-supported, 4, 11, 23, 34
receptor
µ-opiate, ligands, 178
adrenergic, 324
androgen, 327
classes 1, 2 and 3, 324
dopamine, 324
estrogen, 327
G protein-coupled, 100, 101, 196,
170, 173, 236, 247, 250, 251, 254,
255, 257, 258, 285, 306, 323, 325,
326, 329
glucocorticoid, 327
lectin, 302
mineralcorticoid, 327
monoamine, 324
nuclear, 323, 327
orphan, 324
peroxisome proliferator-activated
(PPAR), 328
progesterone, 327
retinoid acid, 327
serotonin, 324
urotensin-II, 195
vitamin D, 327
recursive partitioning (RP), 153
reflectrometry, 296
regression
linear, 366
multiple linear (MLR), 366
partial least square, 367
relationship
linear free energy, 370, 371, 375
multiparameter structure activity
(MSAR), 317, 332
quantitative structure property,
369–371, 373
structure liability (SLR), 317, 319,
332
structure-activity (SAR), 203, 282,
387, 388
structure-property, 366
relaxation, NMR, 266, 276
reporter gene expression, 251
reporter ligand, 276
resin
macroporous, 6
resin
Marshall, 43
resin
Merrifield, 39
resin
polystyrene (PS), 6
resin
scavenger, 4, 25
resin
Wang, 40
resolution, 388, 389, 394, 401
resonance
nuclear magnetic (NMR), 195,
263–274, 276–278, 283, 284, 287,
352
surface plasmon (SPR), 296, 298
416 Subject IndexResofurin, 236
responsive element
cAMP, 254
TPA, 254
RGD motif, 95, 96, 285
rheumatoid arthritis, 390
riboflavin synthase, 277, 278
Rluc, see Luciferase Renilla
rosiglitazone
synthesis, 8, 9
rotatable bonds, 170
RP, see recursive partitioning
Rule-of-Five, see Lipinski’s “rule of
five”
Rule-of-Three, 102
S9 fraction, 351
Salmeterol
synthesis, 9, 10
samples,
liquid, 213
powder, 212
SAR, see structure-activity relationship
SAR-by-NMR, 103, 274, 275, 282
SARM, see modulator, selective androgen receptor
saturation transfer difference (STD),
268, 270, 285, 286
saturation transfer double difference
(STDD), 277, 286, 287
scaffold
decoration, 99
natural product, 103, 104
non-peptidic, 192
novel, 97
privileged, 97
scaling
allometric, 352
scanning, 388, 393, 394
scavenger
fluorous, 42, 43
scavenger
polymer-supported, 4
screening
competition-based, 275
fragment-based, 265, 266
high throughput (HTS), 203, 209,
211, 212, 214, 216–220, 233–235,
237, 240, 241, 247, 249, 251,
254–257, 259, 315, 316, 320,
332, 336, 338, 349, 350, 358,
386, 387
high-content (HCS), 208, 386–403
in silico, 128, 264, 265
protein phosphatase 1B, 282
riboflavin synthase, 277
ultra-high-throughput, 207, 215, 306
virtual, 128, 194, 336
screening methods, 292, 295
atomic force microscopy, 299
biosensor-based, 292, 299
cell-based, 300
chemiluminescence, 292, 297
colorimetric, 292, 296, 297
electrochemical, 292, 299
fiber-optic, 299
fluorescence, 292, 296
label-free optical, 298
laser detection, 299
mass spectrometric, 298
NMR-based, 263ff
radioisotope, 292, 297
reflectivity-based, 298
SEAP, see phosphatase, secreted placental alkaline
second messenger, 400
SELDI-MS, see mass spectrometry,
surface-enhanced laser
desorption/ionization
selectivity, 322, 337, 338
sensitivity, 208
signal
chemiluminescent, 236
fluorescent, 236
signal transduction
peptide arrays, 302
sildenafil synthesis, 7
Similog keys, 144
singleton, 165
singular-value decomposition (SVD),
148
SLR, see relationship, structure liability
Subject Index 417Society for Biomolecular Screening
(SBS), 204, 215
solid-phase organic (SPOS) synthesis,
4
solubility, 343, 346–348, 350, 365,
374, 376
calculation of, 128
equilibrium, 345
intrinsic, 343
thermodynamic, 343, 345
sonochemistry, 37–40
in biocatalysis, 40
organometallic, 38
SPA, see assay, scintillation proximity
space
3-dimensional, 92, 103
biological, 93, 169
chemical, 93, 169
conformational, 196
pharmacophore, 113
SPE, see extraction, solid-phase
SPE, see stochastic proximity embedding
specificity, 323, 324
spectroscopy
fluorescence correlation (FCS), 208,
238
transverse relaxation-optimized
(TROSY), 268
UV, 341
water-ligand observed via gradient,
271, 276, 287
spectrum
19F, 279–281
spin labels, paramagnetic, 276
split-and-mix
synthesis concept, 93
SPOS, see synthesis, solid-phase
organic
SPOT, see synthesis, SPOT
SPR, see resonance, surface plasmon
stability
protein, 304
state index
atom-type electrotopological, 365
STD, see saturation transfer difference
STDD, see saturation transfer double
difference
stochastic proximity embedding, 141,
150
storage
automated, 212
storage conditions, 212
structural fragments, 144
structural similarity, 119
structure-activity relationship (SAR),
146, 147, 177, 186, 265, 274
subset classification, 151
substitution scan, 191
substructure key, 144
support vector machine (SVM), 368
surface area, 376
surface coating
non-binding, 209
surface tension, 204, 225
surrogate, 337, 364
Suzuki coupling
microwave-assisted fluorous phase,
47
microwave-enhanced, 35
sonochemical, 38
SVD, see singular-value decomposition
SVM, see support vector machine
synthesis
angiotensin-II receptor antagonists,
36
automated, 19, 21, 23
biologically active molecules, 7, 12,
19
combinatorial, 14, 93
diversity-oriented, 168
epothilone C, 10, 11
flow-through, 23
histone deacetylase (HDAc)
inhibitors, 22
in situ, 291, 293
IRORI, 291
library, 4, 12, 20, 23, 27
light-directed, 291, 293, 300
418 Subject Indexmicro-mirror device, 291
microwave, 14, 33ff
natural products, 10
oligonucleotide, 293
parallel, 42, 291, 292, 306
peptidase inhibitors, 15–18, 35, 36
photolithographic, 291, 293
polymer-assisted solution phase
(PASP), 4, 7, 19
polysporin, 13
rosiglitazone, 8, 9
salmeterol, 9, 10
sildenafil, 7
solid-phase organic (SPOS), 4, 34,
37, 42
solid-phase peptide, 293
split-and-mix, 93, 44, 117, 291, 293,
296, 306
SPOT, 185, 291–293, 301
Ultrasound, see sonochemistry
Synthon
ammonia, 43
system
expression, 248
integrated discrete multiorgan cell
culture (IdMOC), 357
microfluidic, 226
optical imaging, 231
TAG, see air gap trailing
tagging
fluorous, 44
Tanimoto coefficient, 119, 139, 167
TEER, see transepithelial electrical
resistance
testing
hypothesis, 365
thioesterase, 61
thrombin
inhibitor, 193, 194
titration
acid-base, 341
TNF-a, see tumor necrosis factor-a
toxicity, 327, 354, 356, 357, 365, 380,
386, 387, 390, 397
TPA, see responsive element, TPA
tPSA, see polar surface area, topological
trafficking
protein, 304
training descriptor, 366
training set, 145, 366
transcription factor, 390, 397
transduction
signal, 250, 302
transepithelial electrical resistance
(TEER), 348
transfer
fluorescence energy, 208
transferase
chloramphenicol acetyl (CAT), 251
PKS-associated, 63
Translocation
nuclear, 390, 391, 393, 394
protein, 391
TRF, see fluorescence, energy transfer
TROSY, see spectroscopy, transverse
relaxation-optimized
trueness, 217, 222
tumor necrosis factor-a (TNF-a), 228,
390, 391
turn
peptide: α-, β- & γ-, 190
tyrphostin, 174
ubiquitination, 390
Ugi reactions
microwave-assisted fluorous phase,
47
uHTS, see screening, ultra-highthroughput
ultrasound synthesis, see sonochemistry
uretupamine, 302
Ussing chamber, 348
Veber filter, 127, 170
vector, 248
viability
cell, 390
Subject Index 419420 Subject Index
virus
cytomegalo (CMV), 249
Epstein-Barr (EBV), 248
hepatitis C, 254
Herpes simplex, 249
viscosity, 225
WaterLOGSY, see spectroscopy, waterligand observed via gradient
XL665, see allophycocyanin
X-ray structure
protein tyrosine phosphatase 1B,
284
YFP, see protein, yellow
fluorescent
Z’ factor, 218, 219


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كتاب Exploiting Chemical Diversity for Drug Discovery
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